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dc.contributor.authorRibas, R
dc.contributor.authorPancholi, S
dc.contributor.authorRani, A
dc.contributor.authorSchuster, E
dc.contributor.authorGuest, SK
dc.contributor.authorNikitorowicz-Buniak, J
dc.contributor.authorSimigdala, N
dc.contributor.authorThornhill, A
dc.contributor.authorAvogadri-Connors, F
dc.contributor.authorCutler, RE
dc.contributor.authorLalani, AS
dc.contributor.authorDowsett, M
dc.contributor.authorJohnston, SR
dc.contributor.authorMartin, L-A
dc.date.accessioned2018-06-07T08:34:52Z
dc.date.issued2018-06-08
dc.identifier.citationBreast cancer research : BCR, 2018, 20 (1), pp. 44 - ?
dc.identifier.issn1465-5411
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1751
dc.identifier.eissn1465-542X
dc.identifier.doi10.1186/s13058-018-0983-1
dc.description.abstractBackground Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility.Methods A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies.Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001.Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER.
dc.formatElectronic
dc.format.extent44 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectNeoplasms, Hormone-Dependent
dc.subjectTamoxifen
dc.subjectQuinolines
dc.subjectEstradiol
dc.subjectEpidermal Growth Factor
dc.subjectReceptor, erbB-2
dc.subjectReceptor, erbB-3
dc.subjectEstrogen Receptor alpha
dc.subjectAromatase Inhibitors
dc.subjectEstrogens
dc.subjectSignal Transduction
dc.subjectCell Proliferation
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectFemale
dc.subjectMCF-7 Cells
dc.subjectEverolimus
dc.subjectMechanistic Target of Rapamycin Complex 1
dc.subjectFulvestrant
dc.titleTargeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2018-05-10
rioxxterms.versionofrecord10.1186/s13058-018-0983-1
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-06-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBreast cancer research : BCR
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume20
pubs.embargo.termsNot known
icr.researchteamEndocrine Therapy Resistanceen_US
icr.researchteamEndocrinologyen_US
dc.contributor.icrauthorSchuster, Eugeneen
dc.contributor.icrauthorNikitorowicz-Buniak, Joannaen
dc.contributor.icrauthorJohnston, Stephenen
dc.contributor.icrauthorDowsett, Mitchen
dc.contributor.icrauthorPancholi, Sunilen
dc.contributor.icrauthorMartin, Lesley-Annen


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